The release of injurious constituents from cells has been shown to play an essential role in the mediation of many forms of immunologic tissue injury. We are now faced with problems of how the cells are stimulated to release and by what mechanisms the injurious constituents are discharged into the surrounding milieu. The studies will be conducted on neutrophils, platelets, and mast cells. Immunologic stimuli, or products to immunologic reactions such as active fragments of complement components will be used to examine the release processes in three general ways. 1) The nature of the receptors on the cells for the different stimuli will be studied in whole cells and isolated membranes. The binding of the stimuli to the receptors and their effect on isolated receptors which allows initiation of the biochemical pathway of the release process will be examined. 2) The nature of this pathway will be investigated using inhibitors to delineate cellular requirements for the release and to show the order of their interaction. Attempts will also be made to isolate directly the early components of the pathway, in particular, the activatable serine esterase believed to be involved in activation of these cell types. 3) Morphological examination in the light and electron microscope will be used in order to link biochemical pathways to morphological release mechanisms. In vitro observations will be related to models of immunologic disease to determine which are operative in vivo. The stimuli responsible for changes in the cells in particular inflammatory reactions, will be identified. Inhibitors of in vitro release will also be studied in vivo by parenteral administration or by inhibiting cells in vitro and then using such cells to reconstitute animals previously depleted of this cell type. In this way, it is hoped to obtain more detailed information on the pathogenesis of variety of diseases and also to discover ways in which they may be treated by blocking the mediation sequence.